Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors

Xavier Sisquella, Yifat Ofir-Birin, Matthew A. Pimentel, Lesley Cheng, Paula Abou Karam, Natália G. Sampaio, Jocelyn Sietsma Penington, Dympna Connolly, Tal Giladi, Benjamin J. Scicluna, Robyn A. Sharples, Andreea Waltmann, Dror Avni, Eli Schwartz, Louis Schofield, Ziv Porat, Diana S. Hansen, Anthony T. Papenfuss, Emily M. Eriksson, Motti Gerlic, Andrew F. Hill, Andrew G. Bowie () and Neta Regev-Rudzki ()
Additional contact information
Xavier Sisquella: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Yifat Ofir-Birin: Weizmann Institute of Science
Matthew A. Pimentel: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Lesley Cheng: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Paula Abou Karam: Weizmann Institute of Science
Natália G. Sampaio: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Jocelyn Sietsma Penington: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Dympna Connolly: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2
Tal Giladi: Weizmann Institute of Science
Benjamin J. Scicluna: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Robyn A. Sharples: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Andreea Waltmann: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Dror Avni: The Institute of Geographic Medicine & Tropical Diseases and The laboratory for Tropical Diseases Research, Sheba Medical Center
Eli Schwartz: The Institute of Geographic Medicine & Tropical Diseases and The laboratory for Tropical Diseases Research, Sheba Medical Center
Louis Schofield: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Ziv Porat: Flow Cytometry unit, Life Sciences Core Facilities, Weizmann Institute of Science
Diana S. Hansen: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Anthony T. Papenfuss: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Emily M. Eriksson: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade
Motti Gerlic: Sackler Faculty of Medicine, Tel Aviv University
Andrew F. Hill: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
Andrew G. Bowie: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2
Neta Regev-Rudzki: Weizmann Institute of Science

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite (Plasmodium falciparum) or other pathogen DNA. As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear. Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA. Upon internalization of DNA-harboring EVs by human monocytes, P. falciparum DNA is released within the host cell cytosol, leading to STING-dependent DNA sensing. STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression. This DNA-sensing pathway may be an important decoy mechanism to promote P. falciparum virulence and thereby may affect future strategies to treat malaria.

Date: 2017
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DOI: 10.1038/s41467-017-02083-1

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